The document summarizes a study that investigated whether adding hyaluronidase to ropivacaine reduces the time to achieve complete sensory block after axillary brachial plexus block. Patients were randomly assigned to receive ropivacaine with or without hyaluronidase. The study found that the group receiving ropivacaine with hyaluronidase had a significantly shorter mean time to achieve complete sensory block, sensory block onset time, and time to reach surgical anesthesia compared to the control group receiving ropivacaine alone. Addition of hyaluronidase to ropivacaine resulted in faster blockade times for axillary brachial plexus blocks.

1. Original Article
Use of hyaluronidase as an adjuvant to ropivacaine to reduce
axillary brachial plexus block onset time: a prospective,
randomised controlled study
W. U. Koh,1
H. G. Min,1
H. S. Park,2
M. H. Karm,2
K. K. Lee,3
H. S. Yang4
and Y. J. Ro4
1 Clinical Assistance Professor, 2 Resident, 3 Clinical Lecturer, 4 Professor, Department of Anesthesiology and Pain
Medicine, University of Ulsan, Asan Medical Center, Seoul, Korea
Summary
When considering brachial plexus block as a practical alternative to general anaesthesia for upper limb surgery, the
time to achieve complete sensory block is a clinically important variable. In this prospective randomised double-blind
controlled trial, we investigated the hypothesis that addition of hyaluronidase to ropivacaine may reduce the time to
achieve complete sensory block after axillary brachial plexus block. The patients were randomly assigned into a hyal-
uronidase group (n = 24) and a control group (n = 24). The hyaluronidase group received ropivacaine 0.5% with
100 IU.mlÀ1
of hyaluronidase, and the control group received ropivacaine alone. The primary endpoint was the time
to achieve complete sensory block. The hyaluronidase group demonstrated significantly shorter mean (SD) sensory
block onset time (13.8 (6.0) min) compared with the control group (22.5 (6.3) min, p < 0.0001). Addition of hyal-
uronidase to ropivacaine resulted in a reduction in the time needed to achieve complete sensory block.
.................................................................................................................................................................
Correspondence to: H. G. Min
Email: anesthmin@hanmail.net
Accepted: 20 August 2014
Introduction
Brachial plexus blocks are useful for anaesthesia and
postoperative pain control in surgery performed on
the upper limbs [1, 2]. The axillary approach blocks
the brachial plexus at the terminal branch and pro-
vides anaesthesia suitable for surgery performed on the
forearm [3, 4]. The axillary brachial plexus is superfi-
cial in location, and has no risk of complications such
as pneumothorax or phrenic nerve paralysis that can
occur with other brachial plexus approaches [3, 5].
The widespread use of ultrasound guidance and nerve
stimulation has improved the reliability of axillary bra-
chial plexus blocks, yielding higher success rates with a
reduced number of needle passes [6, 7]. Time to
achieve complete sensory block is clinically important,
as it may influence the decision of whether or not to
perform a brachial plexus block, especially in theatres
where turnover time is an important factor [8, 9].
Hyaluronidase depolymerises hyaluronic acid,
which is a major component of the extracellular
matrix. Through this mechanism of action, hyaluroni-
dase is known to accelerate the onset and improve the
quality of anaesthesia for retrobulbar, peribulbar and
subcutaneous infiltration blocks by increasing the
spread and dispersion of local anaesthetics [10–12].
In the present study, we hypothesised that addi-
tion of hyaluronidase to a local anaesthetic would
reduce the time to achieve complete sensory block of
282 © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70, 282–289 doi:10.1111/anae.12879

2. an axillary brachial plexus block compared with that
of the local anaesthetic alone.
Methods
This prospective, randomised, double-blind, single-
centre trial was conducted at the Asan Medical Center
in Seoul, Republic of Korea. Permission to conduct this
study was approved by the Institutional Review Board of
Asan Medical Center, and written informed consent was
received from each patient who participated in the
study. This study was registered at the Clinical Research
Information Service (cris.nih.go.kr/KCT0000964).
Adult patients (> 19 years of age) scheduled for
elective surgery of the forearm and hand who were
classified as ASA physical status 1–2 were considered
eligible for inclusion in the study. Patients presenting
with neurological deficits of the upper arm, severe co-
agulopathy, chronic obstructive pulmonary disease,
cardiopulmonary compromise, chronic renal failure,
cerebral vascular disease, pregnancy, chronic cortico-
steroid use, hypersensitivity to hyaluronidase or local
anaesthetics or local infection at the site of the axillary
block were excluded from the study.
After enrolment, patients were randomly assigned
into two treatment groups: a hyaluronidase group and a
control group. A computer-generated randomisation
program was used, and patients were allocated just
before performing the block. Study drugs were prepared
in unidentifiable syringes by a staff member who was
not involved in the study. The hyaluronidase group
received ropivacaine mixed 0.5% with 100 IU.mlÀ1
hyaluronidase (H-LASEâ
; KuhnilPharm, Seoul, Korea)
for the axillary brachial plexus block, with the total dose
of hyaluronidase not exceeding 3000 IU. The control
group received ropivacaine 0.5% alone.
All blocks were performed in the operating room
by the first author (WUK). Patients were not pre-
medicated and standard monitors including electrocar-
diography, non-invasive arterial pressure and pulse
oximetry were used. Five litres.minÀ1
of oxygen were
delivered via a facemask and 1 mg midazolam and
50 lg fentanyl were administered intravenously
(regardless of age or weight) for patient comfort dur-
ing the block procedure.
Subjects were positioned supine with the head
turned to the contralateral side and the ipsilateral arm
abducted with the elbow flexed. The skin was disinfec-
ted and infiltrated with lidocaine 1% before block nee-
dle insertion. After sterile drapes were applied, the
ultrasound probe was positioned vertically in the axilla
to obtain a short-axis view of the axillary artery. A 15–
16 MHz high-frequency linear array transducer
(HGL50x; SonoSite, Bothell, WA, USA) and ultrasound
system (S-NerveTM
; SonoSite) were used. The probe
position was further adjusted to achieve a clear view of
the musculocutaneous nerve on the left side of the
ultrasound screen and the axillary artery in the middle
or slightly to the right side of the screen. For musculo-
cutaneous blockade and axillary brachial plexus block,
skin puncture was generally performed once, although
skin puncture was performed twice in patients where
the musculocutaneous nerve was identified in a deep
position or with a large muscle bulk. Using real-time
ultrasound guidance, a 22-G, 60-mm stimulating nee-
dle (Stimuplexâ
D; B.Braun AG, Melsungen, Germany)
was advanced in-plane initially towards the musculo-
cutaneous nerve. A nerve stimulator (MultiStim SEN-
SOR; PAJUNKâ
GmbH Medizintechnologie, Geisingen,
Germany) was used to localise the nerves using an
electrical current of 0.3–0.5 mA while observing
twitches of the corresponding muscle, and 5–7 ml
ropivacaine 0.5% with or without hylauronidase was
injected around the nerve. The needle was then
advanced to a four to six o’clock position (radial
nerve) relative to the axillary artery and after confir-
mation by nerve stimulation, 5–10 ml local anaesthetic
was delivered. The needle was withdrawn and
advanced to the two (ulnar nerve) and 10 (median
nerve) o’clock positions and 5–7 ml local anaesthetic
was sequentially injected in both positions [6, 13].
All surgery was performed with axillary brachial
plexus block as the sole anaesthetic technique. The need
for a supplementary block or conversion to general
anaesthesia was determined by the attending anaesthe-
tist 30 min after the last local anaesthetic injection. Dur-
ing the 30-min observation period, any signs of systemic
local toxicity were observed and managed (if present).
The surgeon, blinded to the treatment group, deter-
mined the need for additional local anaesthetic infiltra-
tion at the surgical site. After the operation, patients
were taken to the post-anaesthetic care unit for recovery
and then moved to a general ward or discharged.
© 2014 The Association of Anaesthetists of Great Britain and Ireland 283
Koh et al. | Hyaluronidase for axillary block Anaesthesia 2015, 70, 282–289

3. During block insertion, the needling time, the time
interval between skin infiltration and the last local
anaesthetic injection, was recorded. Immediately after
the block, sensory and motor blockade was assessed in
the distribution of the median, radial, ulnar and mus-
culocutaneous nerves [6, 13]. These were checked from
time 0 (immediately after the block needle exit from
the skin) to 2, 5, 7, 10, 15, 20, 25 and 30 min after the
block. The sensory block was graded on a 3-point scale
(2 = normal sensation, 1 = reduced and 0 = absent)
compared relative to the pinprick sensation of the cor-
responding areas of the contralateral arm. Time to
achieve complete sensory block (the primary outcome
of this study) was defined as the time to reach an
absent sensation in the pinprick test at all four nerve
distributions (or time to reach point 0 in the sensory
block grade). The motor block was also graded on a 3-
point scale (2 = normal, 1 = reduced power, and
0 = paralysis). The maximal sensory score and motor
score were each 8 points, and thus the total sensorimo-
tor score was 16 points. Patients were considered to
have achieved surgical anaesthesia when the total
composite score was ≤ 2 points, with a concomitant
sensory score ≤ 1 point. Total performance time was
defined as the sum of the time to achieve surgical
anaesthesia and needling time. The total dose of ropi-
vacaine for anaesthesia was recorded. All data were
recorded by an observer blinded to the composition of
the injected local anaesthetic solution.
During surgery, additional midazolam or fentanyl
was administered at the discretion of the attending an-
aesthetist and the total injected dose was recorded. No
patients received sedatives other than midazolam or
opioids other than fentanyl during the operation. Post-
operatively, patients received 325 mg paracetamol and
37.5 mg tramadol orally. Intravenous patient-con-
trolled fentanyl analgesia was applied on demand in
patients who underwent surgery involving bone struc-
tures. For rescue analgesia, intravenous tramadol or
hydromorphone was administered if necessary, and the
time to request first-rescue analgesia (which was
defined as the analgesic duration) was recorded. The
duration of the sensory and motor block was checked
every 2 h after operation by the nursing staff, who
were blinded to the study at the post-anaesthetic care
unit or general ward, and the time of complete
sensorimotor recovery was recorded. The duration of
sensory block was defined as the interval between the
last local anaesthetic injection and the complete resolu-
tion of sensation to pinprick in all four territories,
when the total sensory score reached 8 points in the 3-
point scale. The duration of motor block was defined
as the interval between the last local anaesthetic injec-
tion and the recovery of complete motor function in
the hand and forearm, when the total motor score
reached 8 points in the 3-point scale. The intensity of
postoperative pain was examined by nursing staff 8, 16
and 24 h after the operation using an 11-point numer-
ical rating scale (NRS) [14]. The total dose of intrave-
nous tramadol and opioid was recorded (in morphine
equivalents) during a 24-h postoperative period. Upon
discharge, patients were asked to rate their experience
of the anaesthesia using a 7-point Likert scale ques-
tionnaire (7 = very satisfied, 4 = fair, and
1 = extremely unsatisfied) [15]. After discharge,
patients revisited the outpatient clinic at postoperative
day 15 and were asked about complications including
numbness, paraesthesia, altered sensations, pain and
motor deficits (unrelated to the surgery).
The primary endpoint was the time to achieve
complete sensory block. Secondary outcomes were nee-
dling time, the time to achieve surgical anaesthesia,
total performance time, intra-operative and postopera-
tive analgesic requirements, analgesic duration, sensory
and motor block duration, postoperative pain scores
and patient satisfaction with anaesthesia.
The sample size calculation was based on the
primary endpoint. A preliminary test with 10 patients
in each group (the observer was not blinded) was
performed, and a difference of 7 min in time to
achieve complete sensory block was observed between
the two groups with a SD of 7 min. For a two-tailed
t-test with a error of 0.05 and b error of 0.1, 23
patients were required in each group. Twenty-five
patients were enrolled per group, after assuming a 10%
dropout rate due to block failure or complications.
Descriptive statistics and secondary outcome vari-
ables were compared using t-tests. The Mann–Whitney
U-test was used for continuous variables and the chi-
squared test with Yates’ correction or Fisher’s exact
test was used for categorical variables. Continuous
variables were all first assessed for normality using the
284 © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70, 282–289 Koh et al. | Hyaluronidase for axillary block

4. Shapiro–Wilk test. To compare the time to achieve
complete sensory block, time to achieve surgical anaes-
thesia and the proportion of patients not requiring
postoperative analgesics as a time-to-event analysis, the
log rank test was used and a Kaplan–Meier survival
curve was obtained. A value of p < 0.05 was consid-
ered significant and two-sided tests were used for all
experimental outcomes. SigmaPlot version 12.0 (Sistat
Software Inc, Richmond, CA, USA) was used for sta-
tistical analysis.
Results
Between November 2013 and March 2014, 80 patients
who presented for elective hand or forearm surgery
were screened for eligibility. Eighteen patients met the
exclusion criteria and nine patients refused to partici-
pate, while 53 patients agreed to participate in the
study. A further three patients were removed as they
received general anaesthesia due to surgical require-
ment for iliac bone grafts. One patient in the control
group required conversion to general anaesthesia
because of an incomplete block, while one patient in
the hyaluronidase group showed signs of mild systemic
local toxicity a few minutes after local anaesthetic
injection and was given additional midazolam, making
any further data collection impossible due to overseda-
tion. As a consequence, 24 patients who successfully
completed the study protocol were enrolled in each
group. There were no differences in patient and surgi-
cal characteristics between the two study groups
(Table 1). The site of surgery (bone or soft tissue) was
evenly distributed between the two study groups.
Time to achieve complete sensory block, time to
reach surgical anaesthesia and the total performance
time were significantly lower in the hyaluronidase
group (Table 2, Fig. 1). There was no difference in
Table 1 Characteristics of patients receiving axillary brachial plexus block with and without hyaluronidase, and the
surgery undergone. Values are number (proportion) or mean (SD).
Hyaluronidase
(n = 24)
Control
(n = 24)
Sex; M:F 9 (37.5%):15 (62.5%) 14 (58.3%):10 (41.7%)
Age; years 55.1 (14.1) 54.6 (17.2)
Height; cm 160.1 (10.1) 162.0 (10.8)
Weight; kg 64.3 (12.1) 64.4 (14.4)
Surgery
Left:right 10 (41.7%):14 (58.3%) 12 (50%):12 (50%)
Hand:forearm 7 (29.2%):17 (70.8%) 8 (33.3%):16 (66.7%)
Soft tissue:bone 11 (45.8%):13 (54.2%) 11 (45.8%):13 (54.2%)
Duration of surgery; min 70.7 (32.6) 74 (35.2)
Table 2 Block performance and placement details for patients receiving axillary brachial plexus block with and with-
out hyaluronidase. Values are median (IQR [range]), mean (SD) or number (proportion).
Hyaluronidase
(n = 24)
Control
(n = 24) p value
Needling time; min 6 (5–6.75 [4–9]) 5.5 (4–7 [4–10]) 0.776
Time to achieve complete sensory block; min 13.8 (6.0) 22.5 (6.3) < 0.0001
Time to achieve surgical anaesthesia; min 15.6 (6.3) 22.5 (6.9) 0.00074
Total performance time; min 21.8 (6.2) 29.9 (5.8) < 0.0001
Patients under surgical anaesthesia after 30 min 23 (95.8%) 20 (83.3%) 0.348
Patients with supplemental blocks 1 2 (0.1%) 1.000
Conversion into general anaesthesia 0 1 1.000
Total administered fentanyl; lg 54.2 (14.1) 57.3 (17.3) 0.419
Total administered midazolam; mg 3.3 (0.9) 3.2 (1.1) 0.726
Total administered ropivacaine; mg.kgÀ1
2.2 (0.5) 2.2 (0.5) 0.617
Total administered ropivacaine; mg 138.8 (16.7) 134.8 (18.8) 0.450
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Koh et al. | Hyaluronidase for axillary block Anaesthesia 2015, 70, 282–289

5. needling time, the number of patients under surgical
anaesthesia after 30 min or the number of patients
who required supplemental blocks (Table 2). The total
amount of fentanyl, midazolam and ropivacaine
administered was similar between the two groups
(Table 2).
The duration of the sensory block was shorter in
the hyaluronidase group than in the control group
(Table 3). The duration of the motor block was also
shorter in the hyaluronidase group, but it did not
show statistical significance. The analgesic duration
was shorter in the hyaluronidase group, but it did not
show statistical significance and the numbers of
patients requiring rescue analgesics and the total
postoperative opioid and non-opioid analgesic con-
sumption were not significantly different between the
two groups (Table 3, Fig. 2). Postoperative NRS pain
scores were not significantly different at any of the
(a) (b)
Figure 1 Kaplan–Meier survival plot of proportion of patients who achieved (a) a complete sensory block and (b)
surgical anaesthesia after axillary brachial plexus block with (solid line) and without (dashed line) hyaluronidase.
p < 0.001 vs control.
Table 3 Block duration, analgesic duration, postoperative analgesic requirements, and patient satisfaction with anaes-
thesia after axillary brachial plexus block with and without hyaluronidase. Values are mean (SD) or number (propor-
tion).
Hyaluronidase
(n = 24)
Control
(n = 24) p value
Block duration; min
Duration of sensory block 535.9 (200.2) 671.7 (148.1) 0.010
Duration of motor block 558.4 (235.4) 670.4 (218.7) 0.094
Analgesic duration 610.2 (237.4) 759 (206.2) 0.074
Postoperative (24 h) analgesic requirements
Patients with rescue analgesics 18 (75%) 17 (70.8%) 1.000
Patients with rescue opioids 11 (45.8%) 9 (37.5%) 0.770
Patients with tramadol 17 (70.8%) 13 (54.2%) 0.371
Patients with patient controlled analgesia 10 (41.7%) 8 (33.3%) 0.766
Mean intravenous tramadol; mg 47.9 (37.5) 37.5 (39.7) 0.332
Mean opioid use in morphine equivalents; mg 19.6 (24.4) 13.5 (20) 0.490
Patient satisfaction with anaesthesia
Global perceived effect scale 6.75 (0.44) 6.42 (0.97) 0.259
286 © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2015, 70, 282–289 Koh et al. | Hyaluronidase for axillary block

6. time points (8, 16 and 24 h) examined. Overall satis-
faction ratings for anaesthesia and analgesia were
excellent for both groups (Table 3), and no patients in
either group reported significant neurological symp-
toms or possible complications during admission, after
discharge or at the revisit to the clinic.
Discussion
In the present study, the addition of 100 IU.mlÀ1
of
hyaluronidase to ropivacaine 0.5% significantly short-
ened the time to achieve complete sensory block and
surgical anaesthesia, therefore reducing the anaesthetic
time before the start of the operation. The number of
patients requiring supplementary block or additional
analgesia was similar between the two groups. The use
of hyaluronidase reduced the duration of the sensory
block. The duration of motor block and ropivacaine
brachial plexus block analgesia were also reduced, but
this did not achieve statistical significance. There was
no difference in the total administered dose of postop-
erative analgesic medication.
Reducing the time to reach complete sensory block
has practical advantages, as the turnover time between
operations can be optimised and operation rooms can
be used more efficiently, especially in circumstances in
which there is no separate clinical area to perform a
block [9]. If establishment of a sensory block is pro-
longed, local anaesthetic block may be harder to justify
than general anaesthesia, especially for minor surgery
or in outpatient settings [8]. As a result, many strate-
gies to reduce the total time to reach complete sensory
block during peripheral nerve blocks have been stud-
ied. These strategies include increasing the injection
volume or concentration of local anaesthetics, multiple
injection techniques, alkalinisation of injectate, com-
bining different local anaesthetics or adding adjuvants
such as dexamethasone, dexmedetomidine, clonidine
and magnesium to the local anaesthetic. Alkalinisation
of local anaesthetics has revealed conflicting study
results for hastening the onset of brachial plexus block,
and mixtures of different local anaesthetics have addi-
tive effects in toxicity [16–19]. Some studies that used
dexmedetomidine and clonidine as adjuvants reported
favourable outcomes in terms of reduced total perfor-
mance time [20–22], but most other adjuvants have
failed to demonstrate any superiority over control. A
previous study reported the effect of the addition of
hyaluronidase to bupivacaine 0.5% for axillary brachial
plexus blocks [23]. In that study, 3000 IU hyaluroni-
dase mixed with bupivacaine significantly reduced the
duration of the sensory and motor block, and had no
effect on the number of patients experiencing a com-
plete sensory block after 30 min. These results were
similar to those obtained in the present study, as suc-
cess rates for surgical anaesthesia were similar between
the two experimental groups tested, while the duration
of sensory anaesthesia was significantly shorter in the
hyaluronidase group and the duration of motor block
showed a shorter trend. However, the former study
performed pinprick tests only twice, at 15 and 30 min
after the block placement, so the exact time of com-
plete sensory block was not measured. Furthermore,
the block was conducted via the landmark-guided
technique without the use of a nerve stimulator or
ultrasound guidance, which may have led to the rela-
tively lower block success rate for radial nerve com-
pared with that in our study.
Hyaluronidase is widely used as an adjuvant to
local anaesthetics in regional anaesthesia for ophthal-
mic surgery, where it can reduce onset time and
Figure 2 Kaplan–Meier survival plot of analgesic
duration after axillary brachial plexus block with (solid
line) and without (dashed line) hyaluronidase. Data
points were not studied if the patient did not receive
rescue analgesics. No significant difference between
groups.
© 2014 The Association of Anaesthetists of Great Britain and Ireland 287
Koh et al. | Hyaluronidase for axillary block Anaesthesia 2015, 70, 282–289

7. increase the success rate [24, 25]. A number of studies
have shown that addition of hyaluronidase during
ocular blocks has beneficial effects including higher
quality of anaesthesia and improved success rates [24].
Hyaluronidase has also been used for epidural injec-
tions with local anaesthetics and steroids for control of
chronic back pain [26, 27]. The optimal dose of
hyaluronidase is unknown. For ocular surgery, the
concentration of hyaluronidase varies from 3.75 to
300 IU.mlÀ1
for effective retrobulbar or peribulbar
blocks [25, 28], and for epidural blocks or adhesiolysis
the commonly used dose is 1500 IU [12, 27]. Reports
of adverse effects associated with hylauronidase are
rare, with most reported adverse effects involving aller-
gic reactions to hyaluronidase [24, 29, 30]. No adverse
effects were associated with the use of hyaluronidase
in the present study.
This study has a number of limitations. The time
required to achieve a satisfactory ultrasound image of
the target area was not recorded, although the block
was performed by a single blinded practitioner, and
only a minimal variation in scanning time was
expected. Second, the validity of the 16-point scale to
define surgical anaesthesia can be criticised, as even if
the sensory composite score is 1, a supplementary block
or local infiltration may be required if the incompletely
blocked nerve was the main site of the operation. How-
ever, the 16-point scale has proven to be a useful
method for surgical anaesthesia after brachial plexus
block in many previous studies [6, 8, 21, 31], and none
of the patients who met the criteria for surgical anaes-
thesia in the present study required a supplementary
block or local infiltration. Third, although no adverse
events related to the use of hyaluronidase were reported
during this study, we could not present any definitive
conclusions about the tolerance to hyaluronidase when
used during axillary brachial plexus block as the sample
size was relatively small.
In conclusion, the present study shows that the
use of hyaluronidase as an adjuvant to ropivacaine
reduces the time to reach complete sensory block of
axillary brachial plexus blocks and therefore shortens
the total anaesthetic time before operation. Although it
also reduces the block duration, hyaluronidase had
only a small influence on the total analgesic duration
or the consumption of postoperative analgesics.
Competing interests
No external funding or competing interests declared.
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